1. Field of the Invention
The invention is in the field of organic chemistry. The invention relates to a process for the synthesis of (3R,3′R,6′R)-lutein and its stereoisomers from commercially available (rac)-α-ionone by a C15+C10+C15 coupling strategy. Employing this methodology, (3R,3′R,6′R)-lutein (dietary), (3R,3′S,6′S)-lutein, (3R,3′S,6′R)-lutein (3′-epilutein), and (3R,3′R,6′S)-lutein have been prepared. Based on this strategy, the other 4 stereoisomers of lutein that are enantiomeric to the above lutein isomers can also be prepared. These are: (3S,3′S,6′S)-lutein, (3S,3′R,6′R)-lutein, (3S,3′R,6′S)-lutein, and (3S,3′S,6′R)-lutein.
2. Background Art
(3R,3′R,6′R)-Lutein and (3R,3′R)-zeaxanthin are two dietary carotenoids that are present in most fruits and vegetables commonly consumed in the US. These carotenoids accumulate in the human plasma, major organs, and ocular tissues (macula, retinal pigment epithelium (RPE), ciliary body, iris, lens). In the past decade, numerous epidemiological and experimental studies have shown that lutein and zeaxanthin play an important role in the prevention of age-related macular degeneration (AMD) that is the leading cause of blindness in the U.S. and Western World. While (3R,3′R)-zeaxanthin has been commercially available by total synthesis for more than two decades, the industrial production of (3R,3′R,6′R)-lutein by chemical synthesis has not yet materialized. Consequently, this carotenoid is commercially produced from saponified extracts of marigold flowers. The major difficulty with the total synthesis of (3R,3′R,6′R)-lutein is due to the presence of 3 stereogenic centers at C3, C3′, and C6′ positions in this carotenoid that can result in 8 possible stereoisomers. The chemical structures of 4 of these stereoisomers are shown in Scheme 1. Among these, dietary (3R,3′R,6′R)-lutein (1) and one of its metabolites, (3R,3′S,6′R)-lutein (3′-epilutein) (3), have been detected in human plasma and tissues. The other 4 stereoisomers of lutein (structures not shown), are those in which the configuration at C3 position is S while the stereochemistry at C3′ and C6′ remains the same as those lutein isomers shown in Scheme 1.

To date, the only total synthesis of dietary (3R,3′R,6′R)-lutein (1) has been reported by Mayer and Rüttimann (Helv. Chim. Acta, 1980, 63:1451-55) and is based on the C15+C10+C15 strategy as shown in FIG. 1. According to this methodology, the C15-Wittig salt, (3R)-3-hydroxy-(β-ionylideneethyl)triphenylphosphonium chloride (5), is reacted with one equiv. of 2,7-dimthylocta-2,4,6-triene-1,8-dial (C10-dialdehyde) to give a C25-aldehyde, (3R)-3-hydroxy-12′-apo-β-caroten-12′-al. Both starting materials for this reaction are commercially available and have been employed in the total synthesis of (3R,3′R)-zeaxanthin by the same group. To complete the synthesis of (3R,3′R,6′R)-lutein, Mayer and Rüttimann prepared (3R,6R)-3-acetoxy-α-ionylideneethyl)triphenylphosphonium chloride in 8 steps from (S)-4-hydroxy-2,6,6-trimethyl-2-cyclohexene-1-one in an overall yield of 6.3%. In the final step of this synthesis, these investigators reacted the C25-aldehyde with (3R,6R)-3-acetoxy-α-ionylideneethyl)triphenylphosphonium chloride or bromide to obtain (3R,3′R,6′R)-lutein in 25% yield. Therefore the overall yield for the reported total synthesis of lutein according to this methodology was about 1.6%.
The total synthesis of lutein described in FIG. 1, involves numerous steps and results in a poor overall yield. Consequently, this synthetic approach does not provide an efficient and economically viable route for industrial production of (3R,3′R,6′R)-lutein (1). Therefore, the present invention was developed to provide a more practical route to 1 by employing a divergent synthetic strategy that could be simultaneously applied to the synthesis of other stereoisomers of this carotenoid such as (3R,3′S,6′S)-lutein (2), (3R,3′S,6′R)-lutein (3), and (3R,3′R,6′S)-lutein (4). In addition, this synthetic strategy also provides access to the precursors of optically active carotenoids with 3-hydroxy-ε-end group that are otherwise difficult to prepare.